Cerebrospinal fluid lymphoblasts at diagnosis impact prognosis in B-cell acute lymphoblastic leukemia

Lymphoblasts in diagnostic cerebrospinal fluid samples negatively impacted prognosis in children with B-cell acute lymphoblastic leukemia, regardless of the presence of red blood cells, according to a report from the Children’s Oncology Group.

“Prevention of central nervous system relapse dramatically increases cure rates for children with ALL,” Naomi Winick, MD, from the University of Texas Southwestern Medical Center, and colleagues wrote. “EFS and OS have continued to improve through the application of detailed, risk-based classification systems and large randomized, therapeutic trials. In parallel, the intensity of systemic and intrathecal therapy has increased, and the use of cranial irradiation has largely been eliminated.”

Previous trials showed an association between the presence of lymphoblasts in diagnostic cerebrospinal fluid samples and inferior EFS. However, best approaches to treating those with CNS2 involvement remained unclear, and the data did not reflect the incorporation of current risk stratification schemas or optimal therapies.

To determine the prognostic significance of blasts and white and red blood cells in cerebrospinal fluid samples at diagnosis, Children’s Oncology Group (COG) trials incorporated a uniform cerebrospinal fluid classification system based on the presence of lymphoblasts and the numbers of red and white blood cells from diagnostic samples.

COG trials did not alter therapy for patients with CNS2 disease, defined as less than five white blood cells/µL and blasts with/without 10 or more red blood cells/µL or five or more red blood cells/µL plus blasts, with at least five times the number of white blood cells than red blood cells. However, those with CNS3 disease — defined as at least five white blood cells/µL plus blasts with/without at least 10 red blood cells/µL or clinical signs of CNS disease — received augmented treatment with two extra intrathecal doses during induction and augmented postinduction therapies with cranial irradiation.

Winick and colleagues evaluated the relationship between diagnostic cerebrospinal fluid findings and outcomes in 8,379 children with NCI–categorized standard- and high-risk B-cell ALL treated in 2004 to 2010 COG trials.

Patients received risk-based stratification for postinduction therapy on the basis of clinical variables, lymphoblast genetics at diagnosis and early response to therapy.

In total, 7,395 children reported with CNS1 status (no blasts), 857 with CNS2 status and 127 with CNS3 status.

Of the 7,214 patients with NCI–categorized standard- and high-risk disease without lymphoblasts in the diagnostic cerebrospinal fluid sample, outcomes appeared significantly better for those with standard-risk B-cell ALL.

Children with CNS1 status demonstrated superior 5-year EFS (85%) and OS (92.7%) compared with those with CNS2 status (EFS, 76%; OS, 86.8%) and CNS3 status (EFS, 76%; OS, 82.1%; P < .001).

Multivariable analysis demonstrated that age, white blood cells at diagnosis, race/ethnicity, day 29 minimal residual disease, and cerebrospinal fluid lymphoblasts regardless of cell count independently predicted EFS and OS.

The inferior outcome associated with lymphoblasts in the diagnostic cerebrospinal fluid sample appeared to be associated with an increase in the risk for CNS relapse, but not with the risk for isolated marrow relapse, in patients with CNS1 status compared with CNS2 or CNS3 status (isolated central nervous system relapse, 2% vs. 5.6% vs. 5.1%; P < .001).

“Lymphoblasts in the diagnostic cerebrospinal fluid sample were predictive of an inferior outcome with a statistically significant increase in the cumulative incidence of CNS relapse among the NCI–categorized standard- and high-risk populations,” Winick and colleagues wrote.

“Both CNS2 and CNS3 statuses at diagnosis were associated with an inferior outcome; importantly, the outcome of patients with traumatic lumbar puncture and blasts in their diagnostic cerebrospinal fluid sample was equivalent to those with blasts without red cells.”

The researchers recommended additional augmentation of CNS–directed therapy be used in CNS2 disease.

“Though the small subset of patients with NCI–categorized standard-risk disease who have favorable blast cell genetics and a good response at the end of induction fare well, CNS involvement at any level is an independent predictor of outcome for other patients and warrants consideration of differential CNS–directed therapy to improve outcomes,” they added. – by Kristie L. Kahl

Disclosure: Winick reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.